Over the years, numerous methods have been proposed for improving the delivery of biologically active agents, particularly small molecule drugs. Challenges associated with the formulation and delivery of pharmaceutical agents can include poor aqueous solubility of the pharmaceutical agent, toxicity, low bioavailability, instability, and rapid in-vivo degradation. Although many approaches have been devised for improving the delivery of pharmaceutical agents, no single approach is without its drawbacks. For instance, commonly employed drug delivery approaches aimed at solving or at least ameliorating one or more of these challenges include drug encapsulation (such as in a liposome, polymer matrix, or unimolecular micelle), covalent attachment to a water-soluble polymer (i.e., conjugation) such as polyethylene glycol (i.e., PEG or PEGylation), use of gene targeting agents, and the like.
PEGylation has been employed to improve the bioavailability and ease of formulation of small molecule therapeutics having poor aqueous solubilities. For instance, water-soluble polymers such as PEG have been covalently attached to artilinic acid to improve its aqueous solubility. See U.S. Pat. No. 6,461,603. Similarly, PEG has been covalently attached to triazine-based compounds such as trimelamol to improve their solubility in water and enhance their chemical stability. See International Patent Application Publication No. WO 02/043772. Covalent attachment of PEG to bisindolyl maleimides has been employed to improve poor bioavailability of such compounds due to low aqueous solubility. See International Patent Application Publication No. WO 03/037384. Polymer conjugates of non-steroidal anti-inflammatory drugs (NSAIDs) and of opioid antagonists have also been prepared. See U.S. Patent Application Publication Nos. 2007/0025956 and 2006/0105046, respectively. Prodrugs of camptothecin having one or two molecules of camptothecin covalently attached to a linear polyethylene glycol have also been prepared. See U.S. Pat. No. 5,880,131. Prodrugs of irinotecan and docetaxel having (among other things) four molecules of drug covalently attached to a multi-arm polymer have been described in U.S. Pat. No. 7,744,861 and International Patent Application Publication No. WO 10/019,233, respectively.
The antifolate drug, pemetrexed (available under the ALIMTA® brand as the disodium salt from Eli Lilly and Company, Indianapolis Ind.), exhibits inhibition of thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Approved for treating patients suffering from locally advanced or metastatic nonsquamous non-small cell lung cancer and, in combination with cisplantin, mesothelioma, pemetrexed is also being studied for use in treating patients suffering from other cancers as well.
Use of pemetrexed (like almost all antineoplastic agents) is not without drawbacks. For example, pemetrexed's cytotoxic properties affect both cancerous as well as non-cancerous cells. In particular, pemetrexed is associated gastrointestinal side effects (e.g., nausea, vomiting and anorexia) with a dose-limiting toxicity of myelosuppression. In addition, relatively frequent dosing of the drug is required given pemetrexed's 3.5 hours half-life with 70-90% of the drug excreted unchanged in the urine.
In order to address at least some of these side effects, the use of additional compounds has been proposed. For example, some have proposed the use of folic acid and a methylmalonic acid lowering agent (e.g., vitamin B12) to reduce the toxicity of pemetrexed. See, for example, U.S. Pat. No. 7,772,209.
It would be desirous, however, if pemetrexed could be modified in such a way so as to achieve one or more of the following (i) reduce peak-to-trough variation (with the potential to reduce dose-limiting toxicities), (ii) accumulate in tumor tissues while still retaining efficacy, and (iii) extend the effective half-life to thereby provide less frequent dosing.
The present invention seeks to address these and/or other needs.